Xue Genlong, Yang Jiming, Zhang Yang, Yang Ying, Zhang Ruixin, Li Desheng, Tian Tao, Li Jialiang, Zhang Xiaofang, Li Changzhu, Li Xingda, Yang Jiqin, Shen Kewei, Guo Yang, Liu Xuening, Yang Guohui, Xuan Lina, Shan Hongli, Lu Yanjie, Baofeng Yang, Pan Zhenwei
Department of Pharmacology (The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin, China.
The Institute of Heart and Vascular Diseases, Department of Cardiology, and Central Laboratory, the First Affiliated Hospital of Dalian Medical University, Dalian, China.
Elife. 2025 Jan 7;12:RP89690. doi: 10.7554/eLife.89690.
Dystrophin is a critical interacting protein of Nav1.5 that determines its membrane anchoring in cardiomyocytes. Long noncoding RNAs (lncRNAs) are involved in the regulation of cardiac ion channels, while their influence on sodium channels remains unexplored. Our preliminary data showed that lncRNA- homolog 1 () can bind to dystrophin, which drove us to investigate if can regulate sodium channels by interfering with dystrophin. Western blot and immunofluorescent staining showed that cardiomyocyte-specific transgenic overexpression of (-TG) reduced the membrane distribution of dystrophin and Nav1.5 in cardiomyocytes. Meanwhile, peak was reduced in the hearts of -TG mice than wild-type (WT) controls. The opposite data of western blot, immunofluorescent staining and patch clamp were collected from cardiomyocyte conditional knockout (-cKO) mice. Moreover, increased ventricular arrhythmia susceptibility was observed in -TG mice in vivo and ex vivo. The conservative fragment of inhibited membrane distribution of dystrophin and Nav1.5, and promoted the inducibility of ventricular arrhythmia. Strikingly, activation of transcription by dCas9-SAM system in -TG mice rescued the impaired membrane distribution of dystrophin and Nav1.5, and prevented the occurrence of ventricular arrhythmia. Furthermore, was increased in transaortic constriction (TAC) induced failing hearts, which promoted the inducibility of ventricular arrhythmia. And the expression of is regulated by hydroxyacyl-CoA dehydrogenase subunit beta (hadhb), which binds to and decreases its stability. The human homologue of inhibited the membrane distribution of Nav1.5 in human iPS-differentiated cardiomyocytes. The findings provide novel insights into the mechanism of Nav1.5 membrane targeting and the development of ventricular arrhythmias.
肌营养不良蛋白是心肌细胞中决定Nav1.5膜锚定的关键相互作用蛋白。长链非编码RNA（lncRNAs）参与心脏离子通道的调节，但其对钠通道的影响尚未得到探索。我们的初步数据表明lncRNA-同系物1（）可与肌营养不良蛋白结合，这促使我们研究是否可通过干扰肌营养不良蛋白来调节钠通道。蛋白质免疫印迹和免疫荧光染色显示，心肌细胞特异性转基因过表达（-TG）可降低心肌细胞中肌营养不良蛋白和Nav1.5的膜分布。同时，-TG小鼠心脏中的峰值低于野生型（WT）对照。从心肌细胞条件性敲除（-cKO）小鼠中收集到了蛋白质免疫印迹、免疫荧光染色和膜片钳的相反数据。此外，在体内和体外均观察到-TG小鼠的室性心律失常易感性增加。的保守片段抑制了肌营养不良蛋白和Nav1.5的膜分布，并促进了室性心律失常的诱导性。引人注目的是，在-TG小鼠中通过dCas9-SAM系统激活转录可挽救肌营养不良蛋白和Nav1.5受损的膜分布，并预防室性心律失常的发生。此外，在经主动脉缩窄（TAC）诱导的衰竭心脏中升高，这促进了室性心律失常的诱导性。并且的表达受羟基酰基辅酶A脱氢酶亚基β（hadhb）调节，hadhb与结合并降低其稳定性。的人同源物抑制了人诱导多能干细胞分化的心肌细胞中Nav1.5的膜分布。这些发现为Nav1.5膜靶向机制和室性心律失常的发生发展提供了新的见解。
